Diffuse large B-cell lymphoma (DLCL) is a common lymphoid malignancy in adults, accounting for 30,000 new cases each year and nearly 40% of all non-Hodgkin lymphomas. Although modern treatment can lead to complete remission in a considerable proportion of DLCL patients, many ultimately relapse, probably due to the presence of minimal residual DLCL cells. In this project, we propose to identify relapse of lymphoma at a much earlier time point through detection of personalized lymphoma-specific markers in blood. Specifically, we will use Pyrophosphorolysis Activated Polymerization (PAP), an ultrahigh sensitive nucleic acid amplification technology, to detect as few as one copy of lymphoma-specific somatic mutations in 5 ml of plasma. This assay will be 1000-fold more sensitive than current PCR-based methods. Besides its ultrahigh sensitivity, the testing is non-invasive. The success of this proposal will open new opportunities for personalized monitoring other cancers using similar strategies.